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A recent genome-wide association study (GWAS) identified 12 independent loci significantly associated with attention-deficit/hyperactivity disorder (ADHD). Polygenic risk scores (PRS), derived from the GWAS, can be used to assess genetic overlap between ADHD and other traits. Using ADHD samples from several international sites, we derived PRS for ADHD from the recent GWAS to test whether genetic variants that contribute to ADHD also influence two cognitive functions that show strong association with ADHD: attention regulation and response inhibition, captured by reaction time variability (RTV) and commission errors (CE).
The discovery GWAS included 19 099 ADHD cases and 34 194 control participants. The combined target sample included 845 people with ADHD (age: 8–40 years). RTV and CE were available from reaction time and response inhibition tasks. ADHD PRS were calculated from the GWAS using a leave-one-study-out approach. Regression analyses were run to investigate whether ADHD PRS were associated with CE and RTV. Results across sites were combined via random effect meta-analyses.
When combining the studies in meta-analyses, results were significant for RTV (R2 = 0.011, β = 0.088, p = 0.02) but not for CE (R2 = 0.011, β = 0.013, p = 0.732). No significant association was found between ADHD PRS and RTV or CE in any sample individually (p > 0.10).
We detected a significant association between PRS for ADHD and RTV (but not CE) in individuals with ADHD, suggesting that common genetic risk variants for ADHD influence attention regulation.
Studies in children suggest that neurocognitive performance is a possible endophenotype for ADHD. We wished to establish a first connection between key genetic polymorphisms and neurocognitive performance in adults with ADHD.
We genotyped 45 adults with ADHD at four key candidate polymorphisms for the disorder (DRD4 48 bp repeat, DRD4 120 bp duplicated repeat, SLC6A3 40 bp VNTR, and COMT Val158Met). We then sub-grouped the sample for each polymorphism by genotype or by the presence of the (putative) ADHD risk allele and compared the performance of the subgroups on a large battery of neurocognitive tests.
The COMT Val158Met polymorphism was related to differences in IQ and reaction time, both of the DRD4 polymorphisms (48 bp repeat and 120 bp duplication) showed an association with verbal memory skills, and the SLC6A3 40 bp VNTR polymorphism could be linked to differences in inhibition.
Our findings contribute to the complicated search for possible endophenotypes for (adult) ADHD.
Background: Children diagnosed with medulloblastoma (MB) that are refractory to upfront therapy or experience recurrence have very poor prognoses. Reports of phase I and II studies for these children exist, but bear significant treatment related morbidity and mortality. Methods: A retrospective review of children diagnosed with a pediatric MB from 2002-2015 from the McMaster Pediatric Brain Tumour Study Group (PBTSG) captured a number of pediatric recurrent MB. Results: Over the 13-year period, 31 children with a histological diagnosis of MB were treated. At two years, 21 (67.7%) of 31 patients were free of recurrence and 25 (80.6%) survived. Thirteen children had recurrent or treatment refractory MB. mean time to recurrence was 14.6 months. The mean follow-up for survivors of recurrent MB was 4.0 years. In 3 recurrent MB, the disease had significantly progressed and the patients palliated. For the remaining children, therapy offered included surgery, radiation, and chemotherapy agents either in isolation or in varying combinations. Conclusions: Recurrent MB in our cohort carried a poor prognosis despite administration of salvage therapy. Though there is standardization of the upfront treatment exists, we observed great heterogeneity in the treatment of our 13 patients experiencing recurrence. A greater understanding of the biology of recurrent MB has the potential to guide salvage therapy.
Background: The surgical risk factors and neuro-imaging characteristics associated with cerebellar mutism (CM) remain unclear and require further investigation. We aimed to examine surgical and MRI findings associated with CM in children following posterior fossa tumor resection. Methods: Using our data registry, we retrospectively collected data from pediatric patients who acquired CM and were matched based on age and pathology type with patients not acquiring CM after posterior fossa surgery. The strength of association between surgical and MRI variables and CM were examined using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Results: A total of 22 patients were included. Medulloblastoma was the most common pathology among CM patients (91%). Tumor attachment to the floor of the fourth ventricle (OR, 6; 95% CI, 0.7-276), calcification/hemosiderin deposition (OR 7; 95% CI 0.9-315.5), and post-operative peri-ventricular ischemia on MRI (OR, 5; 95% CI, 0.5-236.5) were found to have the highest association with CM. Conclusions: Our results may suggest that tumor attachment to the floor of the fourth ventricle, pathological calcification, and post-operative ischemia are relatively more prevalent in patients with CM. Collectively, our work calls for a larger multi-institutional study of CM patients to further investigate the determinants and management of CM to potentially minimize its development and predict onset.
Numerous studies have examined relationships between disease biomarkers (such as blood lipids) and levels of circulating or cellular fatty acids. In such association studies, fatty acids have typically been expressed as the percentage of a particular fatty acid relative to the total fatty acids in a sample. Using two human cohorts, this study examined relationships between blood lipids (TAG, and LDL, HDL or total cholesterol) and circulating fatty acids expressed either as a percentage of total or as concentration in serum. The direction of the correlation between stearic acid, linoleic acid, dihomo-γ-linolenic acid, arachidonic acid and DHA and circulating TAG reversed when fatty acids were expressed as concentrations v. a percentage of total. Similar reversals were observed for these fatty acids when examining their associations with the ratio of total cholesterol:HDL-cholesterol. This reversal pattern was replicated in serum samples from both human cohorts. The correlations between blood lipids and fatty acids expressed as a percentage of total could be mathematically modelled from the concentration data. These data reveal that the different methods of expressing fatty acids lead to dissimilar correlations between blood lipids and certain fatty acids. This study raises important questions about how such reversals in association patterns impact the interpretation of numerous association studies evaluating fatty acids and their relationships with disease biomarkers or risk.
Taxometric and behavioral genetic studies suggest that attention deficit hyperactivity disorder (ADHD) is best modeled as a dimension rather than a category. We extended these analyses by testing for the existence of putative ADHD-related deficits in basic information processing (BIP) and inhibitory-based executive function (IB-EF) in individuals in the subclinical and full clinical ranges. Consistent with the dimensional model, we predicted that ADHD-related deficits would be expressed across the full spectrum, with the degree of deficit linearly related to the severity of the clinical presentation.
A total of 1547 children (aged 6–12 years) participated in the study. The Development and Well-Being Assessment (DAWBA) was used to classify children into groups according to levels of inattention and hyperactivity independently: (1) asymptomatic, (2) subthreshold minimal, (3) subthreshold moderate and (4) clinical ADHD. Neurocognitive performance was evaluated using a two-choice reaction time task (2C-RT) and a conflict control task (CCT). BIP and IB-EF measures were derived using a diffusion model (DM) for decomposition of reaction time (RT) and error data.
Deficient BIP was found in subjects with minimal, moderate and full ADHD defined in terms of inattention (in both tasks) and hyperactivity/impulsivity dimensions (in the 2C-RT). The size of the deficit increased in a linear manner across increasingly severe presentations of ADHD. IB-EF was unrelated to ADHD.
Deficits in BIP operate at subclinical and clinical levels of ADHD. The linear nature of this relationship provides support for a dimensional model of ADHD in which diagnostic thresholds are defined in terms of clinical and societal burden rather than representing discrete pathophysiological states.
Attention-deficit hyperactivity disorder (ADHD) is linked to increased risk for substance use disorders and nicotine dependence.
To examine the effects of stimulant treatment on subsequent risk for substance use disorder and nicotine dependence in a prospective longitudinal ADHD case–control study.
At baseline we assessed ADHD, conduct disorder and oppositional defiant disorder. Substance use disorders, nicotine dependence and stimulant treatment were assessed retrospectively after a mean follow-up of 4.4 years, at a mean age of 16.4 years.
Stimulant treatment of ADHD was linked to a reduced risk for substance use disorders compared with no stimulant treatment, even after controlling for conduct disorder and oppositional defiant disorder (hazard ratio (HR) = 1.91, 95% Cl 1.10−3.36), but not to nicotine dependence (HR = 1.12, 95% Cl 0.45−2.96). Within the stimulant-treated group, a protective effect of age at first stimulant use on substance use disorder development was found, which diminished with age, and seemed to reverse around the age of 18.
Stimulant treatment appears to lower the risk of developing substance use disorders and does not have an impact on the development of nicotine dependence in adolescents with ADHD.
Both inhibitory-based executive functioning (IB-EF) and basic information processing (BIP) deficits are found in clinic-referred attention deficit hyperactivity disorder (ADHD) samples. However, it remains to be determined whether: (1) such deficits occur in non-referred samples of ADHD; (2) they are specific to ADHD; (3) the co-morbidity between ADHD and oppositional defiant disorder/conduct disorder (ODD/CD) has additive or interactive effects; and (4) IB-EF deficits are primary in ADHD or are due to BIP deficits.
We assessed 704 subjects (age 6–12 years) from a non-referred sample using the Development and Well-Being Assessment (DAWBA) and classified them into five groups: typical developing controls (TDC; n = 378), Fear disorders (n = 90), Distress disorders (n = 57), ADHD (n = 100), ODD/CD (n = 40) and ADHD+ODD/CD (n = 39). We evaluated neurocognitive performance with a Two-Choice Reaction Time Task (2C-RT), a Conflict Control Task (CCT) and a Go/No-Go (GNG) task. We used a diffusion model (DM) to decompose BIP into processing efficiency, speed–accuracy trade-off and encoding/motor function along with variability parameters.
Poorer processing efficiency was found to be specific to ADHD. Faster encoding/motor function differentiated ADHD from TDC and from fear/distress whereas a more cautious (not impulsive) response style differentiated ADHD from both TDC and ODD/CD. The co-morbidity between ADHD and ODD/CD reflected only additive effects. All ADHD-related IB-EF classical effects were fully moderated by deficits in BIP.
Our findings challenge the IB-EF hypothesis for ADHD and underscore the importance of processing efficiency as the key specific mechanism for ADHD pathophysiology.
Surveying and declaring disease freedom in wildlife is difficult because information on population size and spatial distribution is often inadequate. We describe and demonstrate a novel spatial model of wildlife disease-surveillance data for predicting the probability of freedom of bovine tuberculosis (caused by Mycobacterium bovis) in New Zealand, in which the introduced brushtail possum (Trichosurus vulpecula) is the primary wildlife reservoir. Using parameters governing home-range size, probability of capture, probability of infection and spatial relative risks of infection we employed survey data on reservoir hosts and spillover sentinels to make inference on the probability of eradication. Our analysis revealed high sensitivity of model predictions to parameter values, which demonstrated important differences in the information contained in survey data of host-reservoir and spillover-sentinel species. The modelling can increase cost efficiency by reducing the likelihood of prematurely declaring success due to insufficient control, and avoiding unnecessary costs due to excessive control and monitoring.
Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ.
Multivariate familial models were run on data from 1265 individuals aged 6–18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice–delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI).
Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41–0.71) and IQ (rF=−0.25 to −0.49). The association between ADHD and cognitive performance was largely independent (80–87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ.
The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.
Oppositional defiant disorder (ODD) is frequently co-occurring with attention deficit hyperactivity disorder (ADHD) in children and adolescents. Because ODD is a precursor of later conduct disorder (CD) and affective disorders, early diagnostic identification is warranted. Furthermore, the predictability of three recently confirmed ODD dimensions (ODD-irritable, ODD-headstrong and ODD-hurtful) may assist clinical decision making.
Receiver-operating characteristic (ROC) analysis was used in order to test the diagnostic accuracy of the Conners' Parent Rating Scale revised (CPRS-R) and the parent version of the Strength and Difficulties Questionnaire (PSDQ) in the prediction of ODD in a transnational sample of 1093 subjects aged 5–17 years from the International Multicentre ADHD Genetics study. In a second step, the prediction of three ODD dimensions by the same parent rating scales was assessed by backward linear regression analyses.
ROC analyses showed adequate diagnostic accuracy of the CPRS-R and the PSDQ in predicting ODD in this ADHD sample. Furthermore, the three-dimensional structure of ODD was confirmed by confirmatory factor analysis and the CPRS-R emotional lability scale significantly predicted the ODD irritable dimension.
The PSDQ and the CPRS-R are both suitable screening instruments in the identification of ODD. The emotional lability scale of the CPRS-R is an adequate predictor of irritability in youth referred for ADHD.
After preliminary trials, the detailed changes in the concentration of specific circulating and local antibodies were followed in 15 volunteers inoculated with coronavirus 229E. Ten of them, who had significantly lower concentrations of pre-existing antibody than the rest, became infected and eight of these developed colds. A limited investigation of circulating lymphocyte populations showed some lymphocytopenia in infected volunteers. In this group, antibody concentrations started to increase 1 week after inoculation and reached a maximum about 1 week later. Thereafter antibody titres slowly declined. Although concentrations were still slightly raised 1 year later, this did not always prevent reinfection when volunteers were then challenged with the homologous virus. However, the period of virus shedding was shorter than before and none developed a cold. All of the uninfected group were infected on re-challenge although they also appeared to show some resistance to disease and in the extent of infection. These results are discussed with reference to natural infections with coronavirus and with other infections, such as rhinovirus infections.
Impairments in executive functioning (EF) and intelligence quotient (IQ) are frequently observed in children with attention deficit hyperactivity disorder (ADHD). The aim of this paper was twofold: first, to examine whether both domains are viable endophenotypic candidates for ADHD and second to investigate whether deficits in both domains tend to co-segregate within families.
A large family-based design was used, including 238 ADHD families (545 children) and 147 control families (271 children). Inhibition, visuospatial and verbal working memory, and performance and verbal IQ were analysed.
Children with ADHD, and their affected and non-affected siblings were all impaired on the EF measures and verbal IQ (though unimpaired on performance IQ) and all measures correlated between siblings. Correlations and sibling cross-correlations were not significant between EF and IQ, though they were significant between the measures of one domain. Group differences on EF were not explained by group differences on IQ and vice versa. The discrepancy score between EF and IQ correlated between siblings, indicating that siblings resembled each other in their EF–IQ discrepancy instead of having generalized impairments across both domains. Siblings of probands who had an EF but not IQ impairment, showed a comparable disproportionate lower EF score in relation to IQ score. The opposite pattern was not significant.
The results supported the viability of EF and IQ as endophenotypic candidates for ADHD. Most findings support an independent familial segregation of both domains. Within EF, similar familial factors influenced inhibition and working memory. Within IQ, similar familial factors influenced verbal and performance IQ.
The use of DSM-IV based questionnaires in child psychopathology is on the increase. The internal construct validity of a DSM-IV based model of ADHD, CD, ODD, Generalised Anxiety, and Depression was investigated in 11 samples by confirmatory factor analysis. The factorial structure of these syndrome dimensions was supported by the data. However, the model did not meet absolute standards of good model fit. Two sources of error are discussed in detail: multidimensionality of syndrome scales, and the presence of many symptoms that are diagnostically ambiguous with regard to the targeted syndrome dimension. It is argued that measurement precision may be increased by more careful operationalisation of the symptoms in the questionnaire. Additional approaches towards improved conceptualisation of DSM-IV are briefly discussed. A sharper DSM-IV model may improve the accuracy of inferences based on scale scores and provide more precise research findings with regard to relations with variables external to the taxonomy.
The construct representation of the cross-informant model of the Child Behavior Checklist
(CBCL) and the Teacher Report Form (TRF) was evaluated using confirmatory factor
analysis. Samples were collected in seven different countries. The results are based on 13,226
parent ratings and 8893 teacher ratings. The adequacy of fit for the cross-informant model
was established on the basis of three approaches: conventional rules of fit, simulation, and
comparison with other models. The results indicated that the cross-informant model fits
these data poorly. These results were consistent across countries, informants, and both
clinical and population samples. Since inadequate empirical support for the cross-informant
syndromes and their differentiation was found, the construct validity of these syndrome
dimensions is questioned.
Extraskeletal myxoid chondrosarcoma presenting in the head and neck is extremely rare. Histological diagnosis is difficult and requires close co-operation between clinician, radiologist and pathologist. The tumour has a good prognosis in comparison to myxoid chondrosarcoma of the bone but surgical resection may be difficult due to its gelatinous nature. We present a case of extraskeletal myxoid chondrosarcoma originating in the external auditory meatus of a 42-year-old man. This is the first report of this tumour in this site.
Pyoderma gangrenosum affecting the nose is rare and this may lead to diagnostic confusion because of the large differential diagnosis. As diagnosis is made, largely, on the basis of exclusion the treatment of pyoderma gangrenosum may be unduly delayed. The condition is often disfiguring, particularly following inappropriate surgical intervention, and early diagnosis is therefore important.
We present a case of pyoderma gangrenosum managed initially in the community with minor surgery and resulting in the rare complication of saddle nose deformity.
Surveys with ISO (Kessler et al 1996), in particular with the CAM (Cesarsky et al 1996) and PHOT (Lemke et al 1996) instruments, will greatly extend our understanding of extra-galactic populations and their cosmological evolution. The main advantages that ISO surveys have over e.g IRAS are increased sensitivity/depth and wavelength coverage. Within the Guaranteed and Open Time programmes there are many field surveys which will efficiently map the limits in these parameters. In this talk I will briefly overview those surveys before concentrating in more detail on one survey in particular, the ISO survey of the Hubble Deep Field (HDF), to illustrate the kind of results that can be expected.
Locomotion is recognized as an important aspect of behaviour and knowledge of the locomotion of broiler chickens is important for their health and welfare (Lewis and Hurnik, 1989). Würbel (1995) suggested that certain behaviours can give an indication of poor welfare and that preference tests may be used to ‘fine tune’ a housing system.